Zhenyu Zhang, Alison K. Carlisle, Hamish P. Carter, Joshua R. Lowe, Menekşe Mutlu-Smith, Wendy Lee, Odette Leiter, Shilong Zhang, Annie Harding, Muhammed Syed, David Brici, Rupert W. Overall, Nicole Rund, Christina Steinhauer, Daniel G. Blackmore, Scott Ayton, Ashley I. Bush, Miaona Chen, Gerd Kempermann, Sheng‐Tao Hou, Tara L. Walker
Adult hippocampal neurogenesis declines with age, but the stress pathways that shape neural precursor cell (NPC) survival and lineage progression remain incompletely understood. Here, we tested whether ferroptosis-related vulnerability contributes to the regulation of hippocampal NPCs and their progeny. Using in vitro assays, transcriptomic analyses, and in vivo genetic and pharmacologic perturbations, we find that NPCs show features consistent with elevated susceptibility to ferroptotic stress relative to more differentiated hippocampal populations. Reducing glutathione peroxidase 4 (GPX4) or increasing ferroptotic stress impairs neurogenesis-associated cellular and behavioral phenotypes, whereas pathway modulation improves selected outcomes in aged animals. These effects were context dependent, with distinct consequences across age and behavioral paradigms. Together, the findings support a model in which ferroptosis-related susceptibility contributes to the regulation of adult hippocampal neurogenesis and cognition.